Bosentan improves survival in PPH
Bosentan improves survival in PPH
Fri, 23 May 2003 18:30:00
Seattle, WA - Further data suggesting a survival benefit with the oral endothelin antagonist bosentan (Tracleer; Actelion) in patients with pulmonary hypertension was presented here this week at the annual American Thoracic Society meeting.
Preliminary results from the study, suggesting a survival benefit with bosentan at 24 months, were released last month, but the latest data now show this benefit extending out to 36 months.
The retrospective analysis included 169 patients with pulmonary hypertension who were treated with bosentan in the two randomized, double-blind, placebo-controlled studies of the drug used to gain approval and their open-label extensions. Of the patients, 79% were female and 91% had severe disease (WHO class 3 or 4).
The observed survival of these patients was compared with predicted survival if they had received no treatment, which was estimated using a verified equation based on the National Institutes of Health registry of pulmonary hypertension.
Results showed that survival at one, two, and three years was significantly improved with bosentan.
Survival at one to three years on bosentan
To download table as a slide, click on slide logo below
Lead author of this analysis, Dr Vallerie McLaughlin (RUSH-Presbyterian Hospital, Chicago, IL) explained to heartwire that such a comparison with historical estimates of survival was obviously not as compelling as a randomized trial, but a randomized trial against placebo would not be ethical, given that there are other proven therapies for pulmonary hypertension. "This is not a perfect method, but it is the only ethical way to estimate survival benefits in this population," she said. "We have a very effective therapy in the form of epoprostenol (Flolan, GlaxoSmithKline), and so we cannot give a patient placebo long-term."
Developed more than 20 years ago, epoprostenol has proven survival benefits vs placebo, and McLaughlin says she still regards this drug as the "gold-standard" treatment for pulmonary hypertension. But it must be given by continuous IV infusion through a central venous catheter. This has obvious practical disadvantages and also exposes patients to real risk of infection, McLaughlin explained. In addition, it is important that the infusion not be interrupted and patients can often pull the catheter out by mistake and as a result deteriorate quickly, she added.
In contrast, bosentan is given orallyit the only oral drug available for pulmonary hypertensionand is thus much more preferable from a practical point of view. In the current analysis, patients who deteriorated on bosentan may have been given another drug such as epoprostenol and this would have been termed "treatment failure." Results showed that failure-free survival in the bosentan patients (ie, patients who were still alive and had not deteriorated enough to be given a different drug) was 85% at one year, 69% at two years, and 57% at three years.
McLaughlin said a head-to-head study comparing bosentan and epoprostenol is not feasible as the continuous IV infusion necessary for epoprostenol would make the study "impossible to blind and to recruit." Therefore, the only way to estimate survival benefits with bosentan is comparison with historical controls, she added. "The NIH equation may be slightly inaccurate given that it is 20 years old and background therapy has improved since then, but it has been prospectively validated in another population and it's the best we've got," she commented.
Combination therapy: BREATHE-2
McLaughlin noted that although bosentan and epoprostenol are often given together, there is very little information on the benefits of the combination. The first randomized controlled trial of such combination therapyBREATHE-2was also presented at this week's American Thoracic Society meeting but does not shed much light on the issue. It involved 33 patients already on epoprostenol who were randomized to bosentan or placebo. At 12 weeks, the combination group showed a trend toward better hemodynamics, but the placebo group showed a trend toward improved walking distance. "These are nonsignificant differences and the study is really to small to tell us much at all," McLaughlin said.
Bosentan first choice for class 3 patients
McLaughlin said the take-home message from her study was that using bosentan as first-line therapy does no harm. "I would conclude from this analysis that in this population, 80% of whom were class 3 patients, starting treatment with the easier oral drug is a reasonable strategy,", she commented to heartwire. "Then patients can be switched to epoprostenol or the IV drug can be added if symptoms progress." She says she will now treat her class 3 patients in this way.
However, she added, she will continue to use epoprostenol as her first-line treatment of choice in patients presenting with class 4 pulmonary hypertension. "Class 4 patients probably have just a few months to live, and an oral drug such as bosentan can take a few weeks to start working, whereas epoprostenol has shown proven survival benefits in studies of just 12 weeks' duration," she noted.
Teratogenicity not a major problem
Bosentan is associated with abnormal but reversible liver enzyme elevations, and because it is teratogenic it must not be given to women at risk of getting pregnant. But McLaughlin says she does not regard these as major problems. "Although pulmonary hypertension does affect many young women, pregnancy in these patients is associated with such a high mortality rate that we counsel patients very strongly that pregnancy is simply not an option for them. Therefore a teratogenic drug is not an issue for me."
She says, however, that with treatment patients can live long enough to have children using a surrogate mother. '"If patients improve on treatment, their prognosis is excellent. I have one young woman patient who has improved from class 3 to class 1 with epoprostenol and is now leading an entirely normal life," she added.
Seattle, WA - Further data suggesting a survival benefit with the oral endothelin antagonist bosentan (Tracleer; Actelion) in patients with pulmonary hypertension was presented here this week at the annual American Thoracic Society meeting.
Preliminary results from the study, suggesting a survival benefit with bosentan at 24 months, were released last month, but the latest data now show this benefit extending out to 36 months.
The retrospective analysis included 169 patients with pulmonary hypertension who were treated with bosentan in the two randomized, double-blind, placebo-controlled studies of the drug used to gain approval and their open-label extensions. Of the patients, 79% were female and 91% had severe disease (WHO class 3 or 4).
The observed survival of these patients was compared with predicted survival if they had received no treatment, which was estimated using a verified equation based on the National Institutes of Health registry of pulmonary hypertension.
Results showed that survival at one, two, and three years was significantly improved with bosentan.
Survival at one to three years on bosentan
Years |
Survival on bosentan (%) |
Historical estimate of survival on no treatment (%) |
| 96 |
69 |
|
| 89 |
57 |
|
| 86 |
48 |
Lead author of this analysis, Dr Vallerie McLaughlin (RUSH-Presbyterian Hospital, Chicago, IL) explained to heartwire that such a comparison with historical estimates of survival was obviously not as compelling as a randomized trial, but a randomized trial against placebo would not be ethical, given that there are other proven therapies for pulmonary hypertension. "This is not a perfect method, but it is the only ethical way to estimate survival benefits in this population," she said. "We have a very effective therapy in the form of epoprostenol (Flolan, GlaxoSmithKline), and so we cannot give a patient placebo long-term."
Developed more than 20 years ago, epoprostenol has proven survival benefits vs placebo, and McLaughlin says she still regards this drug as the "gold-standard" treatment for pulmonary hypertension. But it must be given by continuous IV infusion through a central venous catheter. This has obvious practical disadvantages and also exposes patients to real risk of infection, McLaughlin explained. In addition, it is important that the infusion not be interrupted and patients can often pull the catheter out by mistake and as a result deteriorate quickly, she added.
In contrast, bosentan is given orallyit the only oral drug available for pulmonary hypertensionand is thus much more preferable from a practical point of view. In the current analysis, patients who deteriorated on bosentan may have been given another drug such as epoprostenol and this would have been termed "treatment failure." Results showed that failure-free survival in the bosentan patients (ie, patients who were still alive and had not deteriorated enough to be given a different drug) was 85% at one year, 69% at two years, and 57% at three years.
McLaughlin said a head-to-head study comparing bosentan and epoprostenol is not feasible as the continuous IV infusion necessary for epoprostenol would make the study "impossible to blind and to recruit." Therefore, the only way to estimate survival benefits with bosentan is comparison with historical controls, she added. "The NIH equation may be slightly inaccurate given that it is 20 years old and background therapy has improved since then, but it has been prospectively validated in another population and it's the best we've got," she commented.
Combination therapy: BREATHE-2
McLaughlin noted that although bosentan and epoprostenol are often given together, there is very little information on the benefits of the combination. The first randomized controlled trial of such combination therapyBREATHE-2was also presented at this week's American Thoracic Society meeting but does not shed much light on the issue. It involved 33 patients already on epoprostenol who were randomized to bosentan or placebo. At 12 weeks, the combination group showed a trend toward better hemodynamics, but the placebo group showed a trend toward improved walking distance. "These are nonsignificant differences and the study is really to small to tell us much at all," McLaughlin said.
Bosentan first choice for class 3 patients
McLaughlin said the take-home message from her study was that using bosentan as first-line therapy does no harm. "I would conclude from this analysis that in this population, 80% of whom were class 3 patients, starting treatment with the easier oral drug is a reasonable strategy,", she commented to heartwire. "Then patients can be switched to epoprostenol or the IV drug can be added if symptoms progress." She says she will now treat her class 3 patients in this way.
However, she added, she will continue to use epoprostenol as her first-line treatment of choice in patients presenting with class 4 pulmonary hypertension. "Class 4 patients probably have just a few months to live, and an oral drug such as bosentan can take a few weeks to start working, whereas epoprostenol has shown proven survival benefits in studies of just 12 weeks' duration," she noted.
Teratogenicity not a major problem
Bosentan is associated with abnormal but reversible liver enzyme elevations, and because it is teratogenic it must not be given to women at risk of getting pregnant. But McLaughlin says she does not regard these as major problems. "Although pulmonary hypertension does affect many young women, pregnancy in these patients is associated with such a high mortality rate that we counsel patients very strongly that pregnancy is simply not an option for them. Therefore a teratogenic drug is not an issue for me."
She says, however, that with treatment patients can live long enough to have children using a surrogate mother. '"If patients improve on treatment, their prognosis is excellent. I have one young woman patient who has improved from class 3 to class 1 with epoprostenol and is now leading an entirely normal life," she added.
|
Source...